Synapse formation is a complex, incompletely understood process that has received only limited investigation in man despite the importance of synaptic dysfunction in common disorders such as epilepsy and mental retardation. This review explores synaptic differentiation, focussing on the morphologic maturation of synapses. Since differentiation depends on many antecedent developmental events, synaptogenesis can be affected by several factors: errors in neuronal proliferation, migration, and differentiation. The challenge to the neurobiologist is to detect and evaluate the minor alterations in neuronal differentiation that could account for the structural basis of the clinical manifestations. Trisomy 21 is an example of a condition in which the cytoarchitecture of the cerebral cortex is not obviously altered, yet mental retardation is consistently present; research neurobiologic techniques are making possible documentation of its structural basis. Epilepsy is another example in which examination of surgically removed cerebral cortex reveals subtle cortical dysplasias helpful in understanding the basis for the abnormal electrical discharge. Further exploration of synaptogenesis, particularly the influence of gene products and epigenetic factors on synapse maturation, will increase our understanding of the pathogenesis of conditions in which "morphology" seems normal but function is abnormal.